1. Field of the Invention
The present invention relates to pharmaceutically active compounds and pharmaceutical compositions and therapeutic methods that comprise such compounds. Preferred compounds of the invention are useful for the treatment or prophylaxis of undesired thrombosis. The invention has a wide spectrum of applications including use in screening candidate compounds for the treatment or prophylaxis of thrombosis.
2. Background
Blood clotting assists hemostasis by minimizing blood loss. Generally, blood clotting is initiated by vessel damage and requires platelet aggregation, coagulation factors and inhibition of fibrinolysis. The coagulation factors act through a cascade that relates the vessel damage to formation of a blood clot (see generally L. Stryer, Biochemistry, 3rd Ed, W. H. Freeman Co., New York; and A. G. Gilman et al., The Pharmacological Basis of Therapeutics, 8th Edition, McGraw Hill Inc., New York, pp. 1311-1331).
Tissue factor (TF), an integral membrane protein of 263 amino acids, is responsible for initiating the coagulation protease cascade. Vascular damage exposes blood to tissue factor expressed on subendothelial cell surfaces, leading to the formation of a calcium-dependent, high-affinity complex with the plasma factor VII (FVII) or activated factor VII (FVIIa). Binding to TF promotes rapid proteolytic cleavage of the zymogen FVII to the active serine protease FVIIa by a number of proteases such as factor Xa, or thrombin. TF also functions as an essential cofactor for FVIIa by dramatically enhancing the catalytic efficiency of FVIIa for its protein substrates factors IX and X. TF/VIIa complex activates factors IX (FIX) and X (FX) via limited proteolysis, ultimately leading to thrombin generation and fibrin deposition. Under pathological conditions such as atherosclerosis or following invasive surgical procedures such as microvascular graft, angioplasty, deployment of an implanted device (e.g., a stent, catheter or arteriovenous shunt), or endarterectomy, TF-initiated coagulation can lead to thrombotic disorders that can result e.g. in heart attack, stroke, unstable angina, graft failure or other coronary disorder.
Thrombosis also may accompany various thromboembolic disorders and coagulopathies such as a pulmonary embolism (e.g., atrial fibrillation with embolization, deep vein thrombosis, etc.) and disseminated intravascular coagulation, respectively. Manipulation of body fluids can also result in an undesirable thrombus, particularly in blood transfusions or fluid sampling, as well as procedures involving extracorporeal circulation (e.g., cardiopulmonary bypass surgery) and dialysis.
Certain anti-coagulants have been used to alleviate or avoid blood clots associated with thrombosis. Blood clotting often can be minimized or eliminated by administering a suitable anti-coagulant or mixture thereof, including one or more of a coumarin derivative (e.g., warfin and dicumarol) or a charged polymer (e.g., heparin, hirudin or hirulog). See e.g., Gilman et al., supra, R. J. Beigering et al., Ann. Hemathol., 72:177 (1996); J. D. Willerson, Circulation, 94:866 (1996).
Certain antibodies with anti-platelet activity have also been used to alleviate various thromboses. For example, ReoPro(trademark) is a therapeutic antibody that is routinely administered to alleviate various thromboembolic disorders such as those arising from angioplasty, myocardial infarction, unstable angina and coronary artery stenoses. Additionally, ReoPro(trademark) can be used as a prophylactic to reduce the risk of myocardial infarction and angina (J. T. Willerson, Circulation, 94:866 (1996); M. L. Simmons et al., Circulation, 89:596 (1994)).
However, use of prior anti-coagulants is often associated with side effects such as hemorrhaging, re-occlusion, xe2x80x9cwhite-clotxe2x80x9d syndrome, irritation, birth defects, thrombocytopenia and hepatic dysfunction. Long-term administration of anti-coagulants can particularly increase risk of life-threatening illness (see e.g., Gilman et al., supra).
Protein-based agents are potentially safer, but generally are limited to treatment of acute conditions and often are restricted to parenteral administration. Such agents are considered less suitable for long-term therapies for chronic diseases (such as atherosclerosis, a major cause of heart attack) due to the increased probability of immune response to a protein therapeutic, relatively high production cost and/or limited oral bioavailability.
It would thus be desirable to have new anti-coagulant agents. It would be particularly desirable to have new anti-coagulant agents that could be administered over a relatively long period to treat chronic conditions such as atherosclerosis.
We have now discovered pharmaceutically active compounds and particularly tissue factor (TF) antagonists that have a wide spectrum of uses including use in the treatment and/or prevention of undesired thrombosis. Preferred compounds of the invention specifically block human factor X and IX activation catalyzed by a human tissue factor/factor VIIa complex. Also discovered are methods for treating or preventing thrombosis that use the compounds and compositions disclosed herein.
More particular methods of this invention include administering a therapeutically effective amount of at least one compound or composition of this invention. The compound or composition is typically given to a mammal in need of such treatment such as a human patient who is susceptible to, suffering from, or recovering from undesired thrombosis, or mammal that is suffering from, recovering from or susceptible to other disease or disorder impacted by tissue factor such as cardiovascular disease, cell proliferation disorder, post-operative complication, or an immune disorder. Preferred compounds and compositions may also be used to treat or prevent recognized disorders impacted by various thromboses such as those particular disorders disclosed herein.
The invention also includes methods for blocking or inhibiting tissue factor-dependent activation of factor X and/or factor IX. These methods in general include contacting tissue factor with a TF blocking compound to thereby inhibit formation of a functional complex of factor X or factor IX with tissue factor or TF/VIIA. Preferably the TF blocking compound binds to tissue factor to thereby inhibit formation of the functional complex. Inhibition or prevention of formation of such a complex in accordance with the invention can have quite broad application, including for treatment of the above-mentioned diseases or disorders in mammals, particularly humans suffering from or susceptible to such diseases or disorders.
Preferred compounds of the invention generally exhibit good blocking activity in at least one test for detecting and preferably measuring TF-mediated blood clotting. More particular tests are standard in vitro assays for measuring activity of a specific blood coagulation factor in which the assay is recognized as providing optimal results in the presence of TF or a TF-associated complex such as the human TF/VIIa complex. The TF can be provided in the assay as a recombinant molecule or molecule purified from natural sources depending usually on the specific assay selected.
A more particular in vitro assay detects and measures activity of a specific blood coagulation factor which has a recognized activity enhanced in the presence of human TF or the human TF/VIIa complex. Of preferred interest are standard in vitro assays for measuring TF-dependent activation of factor X to FXa and factor IX to FIXa. Sometimes these assays will be referred to herein as a xe2x80x9cprimary screening assayxe2x80x9d or related term or phrase such as xe2x80x9cmethod of discoveryxe2x80x9d to denote preferred use of the assay in screening compounds.
For example a particularly preferred compound of the invention will exhibit good blocking activity in the primary screening assay for measuring TF-dependent activation of factor X to FXa. Additionally preferred compounds will exhibit good blocking activity in the primary screening assay for measuring TF-dependent activation of factor IX to FIXa.
It will be appreciated that by the phrase xe2x80x9cgood blocking activityxe2x80x9d or related phrase is meant preferred use of a compound of this invention to reduce or inhibit clotting activation of factor X to FXa and/or factor IX to FIXa. A preferred compound is a synthetic or semi-synthetic compound such as those small molecule compounds disclosed below. More particular disclosure relating to the primary screening assays is provided as follows.
Preferred small molecule compounds of this invention will exhibit an IC50 (concentration required to, inhibit factor X activation by about 50% relative to a suitable control) of about 100 xcexcM or less and preferably about 10 xcexcM or less. Additionally preferred compounds will exhibit equivalent or greater than about 70% inhibition of TF- or TF/VIIa dependent FX activation in the assay. In a preferred embodiment, the primary screening assay includes all of the following steps:
1) admixing in a suitable assay solution TF/VIIa complex and factor X under conditions conducive to forming factor Xa,
2) contacting the solution with a detectably-labeled factor Xa substrate; and
3) detecting labeled product in the solution as being indicative of the factor X activation.
Preferred use of this primary screening assay effectively measures capacity of a candidate compound to decrease or eliminate TF- or TF/VIIa dependent factor X activation. The assay is generally flexible and can be manipulated as necessary to test a compound for capacity to block factor X activation. For example, the candidate compound can be added at any one or more of the steps shown above with addition of the compound at step 1) being preferred for many screening applications.
A preferred TF/VIIa complex for use in the method includes TF which has been exposed to conditions conducive to exposing good TF blocking sites. More specific conditions for isolating and using the TF are provided below.
As mentioned above, another primary screening assay is a standard in vitro assay for measuring factor IX activation by TF or TF/VIIa. In this example, a preferred compound will exhibit an IC50 (concentration required to inhibit factor IX activation in the assay by about 50% relative to a suitable control) in the assay of from between about 200 xcexcM or less, and preferably about 10 xcexcM or less. In a preferred embodiment, the standard assay for measuring the factor IX activation includes all of the following steps:
1) admixing in a suitable assay solution TF/VIIa complex with factor IX under conditions conducive to forming factor FIXa,
2) contacting the solution with a detectably-labeled FIXa substrate; and
3) detecting labeled product in the solution as being indicative of the factor IXa activation by TF/VIIa.
In preferred embodiments, this screening assay effectively measures capacity of the candidate compound to decrease or eliminate Factor IX activation. The assay is generally sensitive to TF- or TF/VIIa-dependent formation of FIXa and can be used in several ways to test a desired compound for capacity to block the factor IX activation. For example, a compound to be further tested can be added at one or more of the steps shown above with addition of the compound at step 1) being preferred for most screening applications. Typically preferred compounds of this invention will exhibit good blocking activity in this example of the primary screening assay.
A further preferred primary screen of the invention is the Prothrombin Time (PT) test or assay which measures extrinsic pathway clotting. This test is standard in the field and is routinely used to measure clotting in biological samples such as blood plasma More particularly preferred compounds of this invention will exhibit good inhibitory activity in the PT assay. A typically preferred compound will increase plasma clotting time in the PT assay relative to a suitable control by at least about 5% to about 10% (seconds). Preferred use of the PT assay measures TF-mediated blood plasma clot time and is performed as follows:
1) providing citrated plasma in a suitable assay solution under conditions conducive to plasma coagulation,
2) admixing a suitable tissue factor preparation and calcium in the solution under conditions suitable for initiating plasma clotting; and
3) measuring the clot time in the solution to determine the prothrombin clot time (PT).
Preferred use of the PT assay measures capability of the compound tested to prolong the prothrombin clot time. The PT assay is well known in this field and can be employed in one or a combination of ways to test the compound for capacity or capability to increase or block the prothrombin clot time.
Especially preferred compounds of this invention exhibit good activity in at least one of the primary assays mentioned above (factor X, factor IX activation and/or PT tests).
Good inhibition of the TF- or TF/VIIa-dependent activation in any one or more of the above primary screening assays at least in many cases can be attributed to effects of the compound on TF/VIIa and/or FXa activities. As discussed, preferred compounds of the invention are TF-antagonists and generally exhibit good blocking activity in preferred in vitro assays for measuring TF-mediated blood coagulation. Thus it will usually be desirable to further test compounds giving good blocking activity in one or more of the above primary screening assays and in at least one and preferably more than one of the xe2x80x9csecondary screening assaysxe2x80x9d discussed below. Such secondary assays can facilitate further identification and selection of candidate compounds having desired TF-antagonist activity, e.g., by eliminating from consideration compounds having activity other than desired activity such as compounds impacting protease activity.
A variety of secondary assays can be conducted in accord with this invention to further evaluate compounds identified in a primary assay, e.g. to further evaluate activity identified in a primary assay or to determine the presence of a certain undesired activity. For example, additionally preferred compounds of this invention will exhibit substantially reduced or negligible activity in other secondary screening assays which are not optimized to measure TF-antagonism. That is, these secondary assays may not be TF dependent. Particular examples of such assays include those formatted to measure thrombin, trypsin, or activated factors such as FXa, FIXa, or FVIIa. Also, preferred compounds exhibit negligible activity in an Activated Partial Thromoplastin Time (APTT) test or assay. More specific examples of such secondary screening assays are provided in the discussion and Examples which follow.
In any one or all of the assays disclosed herein including the primary screens and secondary tests discussed above, the candidate compound can be provided in the assay as the sole active agent or it can be combined with other agents to be tested including other compounds or compositions of this invention. In this embodiment, the screening assays are particularly useful for detecting and preferably quantifying synergism between the compounds, agents or compositions.
A variety of inhibitors against human tissue factor are disclosed herein. These compounds can be used in the screening assays described herein as well as the treatment and prevention methods of this invention.
For example, disclosed herein are certain compounds that are sometimes referenced herein as xe2x80x9cTF antagonistsxe2x80x9d, xe2x80x9cTF blocking compoundsxe2x80x9d or similar phrase. Preferred compounds of the invention are small molecules and do not include peptides.
Preferred TF antagonists have been disclosed in U.S. application Ser. No. 09/406,269, filed Sep. 24, 1999, and corresponding PCT application number PCT/US99/22238, filed Sep. 24, 1999, both incorporated herein by reference. That application discloses inter alia phosphonate compounds, including aryl-substituted phosphonate compounds.
We have now discovered additional TF antagonist compounds that are useful in the methods of the invention.
More particularly, preferred compounds of the invention include one or more of certain polar groups, particularly carboxy (xe2x80x94COOH), amido (i.e. xe2x80x94C(xe2x95x90O)xe2x80x94Nxe2x80x94, either in non-cyclic or cyclic group, and tautomers thereof), thioamido (i.e. xe2x80x94C(xe2x95x90S)xe2x80x94Nxe2x80x94, either in non-cyclic or cyclic group, and tautomers thereof), sulfinyl (xe2x80x94S(O))xe2x80x94, sulfonyl (xe2x80x94S(O)2xe2x80x94), sulfono (SO3) or nitro (NO2) groups. Preferred compounds of the invention include such polar groups together with an aromatic moiety, particularly a carbocyclic aryl group such as phenyl, naphthyl and the like, or a heteroaryl group typically having from 1 to 3 separate or fused rings, 5 to 8 atoms per ring and 1-3 hetero (N, O or S) atoms. The invention also includes non-aromatic compounds.
More specifically, preferred compounds of the invention include those of the following Formula I:
Arxe2x80x94(CXY)mxe2x80x94(Het)0 or 1xe2x80x94(CX1Y1)nxe2x80x94C(Z)pxe2x80x94(T)3xe2x88x92pxe2x80x83xe2x80x83I
Ar is optionally substituted carbocyclic aryl or optionally substituted heteroaryl;
Het is optionally substituted N, O or S;
each T is independently a polar group such as amido (i.e. xe2x80x94C(xe2x95x90O)xe2x80x94Nxe2x80x94, either in non-cyclic or cyclic group, and tautomers thereof), thioamido (i.e. xe2x80x94C(xe2x95x90S)xe2x80x94Nxe2x80x94, either in non-cyclic or cyclic group, and tautomers thereof), carboxy, sulfinyl, sulfonyl, sulfonic (SO3), or nitro group;
each X, each Y, each Xxe2x80x2, each Yxe2x80x2 and each Z are each independently hydrogen; halogen; hydroxyl; sulfhydryl; amino; optionally substituted alkyl preferably having 1 to about 12 carbons, more preferably 1 to about 6 carbons; optionally substituted alkenyl preferably having from about 2 to 12 carbon atoms, more preferably about 2 to 6 carbons; optionally substituted alkynyl preferably having from about 2 to 12 carbon atoms, more preferably about 2 to 6 carbon atoms; optionally substituted alkoxy preferably having 1 to about 12 carbon atoms, more preferably 1 to about 6 carbon atoms; optionally substituted alkylthio preferably having from about 1 to 12 carbon atoms, more preferably about 1 to 6 carbon atoms; optionally substituted alkylsulfinyl preferably having from about 1 to 12 carbon atoms, more preferably about 1 to 6 carbon atoms; optionally substituted alkylsulfonyl preferably having from about 1 to 12 carbon atoms, more preferably about 1 to 6 carbon atoms; or optionally substituted alkylamino preferably having from about 1 to 12 carbon atoms, more preferably about 1 to 6 carbon atoms;
m is an integer of from 0 (where the hetero atom is directly substituted on the aryl group) to 4, and preferably is 0, 1 or 2;
n is an integer of from 0 to 4, and preferably n is 1 or 2;
p is 1 (where the compound has two T groups) or 2 (where the compound has a single T group); and pharmaceutically acceptable salts thereof.
Additional preferred compounds include those of the above formula where Ar is a carbocyclic aryl group, particularly phenyl, such as compounds of the following Formula II: 
wherein X, Y, Het, T, Xxe2x80x2, Yxe2x80x2, Z, m, and p are the same as defined in Formula I above;
wherein each R1 is independently halogen (F, Cl, Br, I); amino; hydroxy; nitro; carboxy; sulfhydryl; optionally substituted alkyl preferably having 1 to about 20 carbon atoms, more preferably 1 to about 10 carbon atoms, still more preferably 1 to about 6 carbon atoms; optionally substituted alkenyl preferably having 2 to about 20 carbon atoms, more preferably 2 to about 10 carbon atoms, still more preferably 2 to about 6 carbon atoms; optionally substituted alkynyl preferably having 2 to about 20 carbon atoms, more preferably 2 to about 10 carbon atoms, still more preferably 2 to about 6 carbon atoms; optionally substituted alkoxy preferably having 1 to about 20 carbon atoms, more preferably 1 to about 10 carbon atoms, still more preferably 1 to about 6 carbon atoms; optionally substituted alkylthio preferably having 1 to about 20 carbon atoms, more preferably 1 to about 10 carbon atoms, still more preferably 1 to about 6 carbon atoms; optionally substituted alkylsulfinyl preferably having 1 to about 20 carbon atoms, more preferably 1 to about 10 carbon atoms, still more preferably 1 to about 6 carbon atoms; optionally substituted alkylsulfonyl preferably having 1 to about 20 carbon atoms, more preferably 1 to about 10 carbon atoms, still more preferably 1 to about 6 carbon atoms; optionally substituted alkylamino preferably having 1 to about 20 carbon atoms, more preferably 1 to about 10 carbon atoms, still more preferably 1 to about 6 carbon atoms; optionally substituted alkanoyl preferably having 1 to about 20 carbon atoms, more preferably 1 to about 10 carbon atoms, still more preferably 1 to about 6 carbon atoms; optionally substituted carbocyclic aryl; or optionally substituted aralkyl;
q is an integer of from 0 (where the phenyl ring positions are fully hydrogen substituted) to 5, and preferably m is 0, 1 2 or 3; and pharmaceutically acceptable salts thereof.
Of the compounds of the above Formulae I and II, additional preferred compounds include those where the group Het is optionally substituted nitrogen or oxygen, such as compounds of the following Formulae III and IV: 
wherein in each of Formula III and IV, T, R1, X, Y, Xxe2x80x2, Yxe2x80x2, Z, q, m, n and p are the same as defined in Formulae I and II above; and W is hydrogen, optionally substituted alkyl, preferably having 1 to about 8 carbon atoms, more preferably 1 to about 6 carbon atoms; optionally substituted alkenyl, preferably having 2 to about 8 carbon atoms, more preferably 2 to about 6 carbon atoms; optionally substituted alkynyl, preferably having 2 to about 8 carbon atoms, more preferably 2 to about 6 carbon atoms; optionally substituted alkoxy, preferably having 1 to about 8 carbon atoms, more preferably 1 to about 6 carbon atoms; optionally substituted alkylthio, preferably having 1 to about 8 carbon atoms, more preferably 1 to about 6 carbon atoms; optionally substituted alkylsulfinyl, preferably having 1 to about 8 carbon atoms, more preferably 1 to about 6 carbon atoms; optionally substituted alkylsulfonyl; optionally substituted alkylamino; optionally substituted alanoyl, preferably having 1 to about 8 carbon atoms, more preferably 1 to about 6 carbon atoms; optionally substituted carbocyclic aryl; or optionally substituted aralkyl; and pharmaceutically acceptable salts thereof.
Additional compounds of Formula III include those where the nitrogen group is a direct (no interposed carbon or other atoms) phenyl ring substituent, and particularly preferred compounds of Formula IV include those where the oxygen is a direct ring substituent or a single methylene group is present, such as compounds of the following Formulae IIIa and IVa: 
wherein T, Rxe2x80x2, X1, Yxe2x80x2, n and q are the same as defined in Formulae I and II above; and pharmaceutically acceptable salts of those compounds.
Additional preferred compounds of the invention include those that have an optionally substituted amine moiety, such as compounds of the following Formula V:
(R2)2Nxe2x80x94(CXY)m1xe2x80x94(Het)0 or 1xe2x80x94(CX1Y1)nxe2x80x94C(Z)pxe2x80x94(T)3xe2x88x92pxe2x80x83xe2x80x83V
wherein each of X, Y, Het, Xxe2x80x2, Yxe2x80x2, Z, T, n, g, p are each the same as defined in Formula I above; each R2 is independently hydrogen alkyl, typically C1-8 alkyl, aryl, typically carbocyclic aryl such as phenyl or naphthyl, and the like; m1 is an integer of from 0 (where the hetero atom is directly substituted with the amine group) to 4, and preferably is 0, 1 or 2. More preferred compounds according to the Formula V include those in which each of X, Y, Xxe2x80x2 and Yxe2x80x2 is independently hydrogen; Het is 0; Z is a hydroxyl group; and each of m1, n and p is 1. Also included are pharmaceutically acceptable salts of the compound shown in Formula V.
Further preferred compounds of the invention include those that have a polycyclic group of at least two aromatic ring structures. More preferred are compounds having the following Formula VI:
Ar1xe2x80x94(CXY)m2xe2x80x94(Het)0 or 1xe2x80x94(CX1Y1)nxe2x80x94C(Z)pxe2x80x94(T)3xe2x88x92pxe2x80x83xe2x80x83VI
wherein each of X, Y, Xxe2x80x2, Yxe2x80x2, Z, n and p is defined as in Formula I above and Ar1 represents a polycyclic aromatic group, preferably an optionally substituted carbocyclic aryl or heteroaryl group having between about 2 to about 3 aromatic rings such as napthyl, acenapthyl and the like, and m2 is an integer of from 0 (where the polycyclic group is directly substituted with the heteroatom) to 4, and preferably is 0, 1, or 2; and pharmaceutically acceptable salts thereof.
Additionally preferred compounds of the Formula VI shown above include those where the Ar1 group represents an optionally substituted biphenyl group, such as those preferred compounds having the following Formula VIa:
(R1)q1xe2x80x94Ar1xe2x80x94(CXY)m2xe2x80x94(Het)0 or 1xe2x80x94(CX1Y1)nxe2x80x94C(Z)pxe2x80x94(T)3xe2x88x92pxe2x80x83xe2x80x83VIa
wherein R1 is the same as defined above in Formula II; and each of X, Y, Xxe2x80x2, Yxe2x80x2, Z, g, n and p is defined as in Formula I above; m2 is the same as defined above in Formula VI; q1 is an integer from 0 (where the biphenyl group is fully substituted with hydrogen) to 7, and preferably q1 is 0, 1, 2, 3, or 4; and pharmaceutically acceptable salts thereof.
In a more preferred embodiment of the Formula VIa shown above, Ar1 is a substituted biphenyl, R1 is hydroxyl, m2 and n are each 0, Het is a nitrogen atom, Z is hydrogen, p is 1, and q1 is 1, 2 or 3; and pharmaceutically acceptable salts thereof.
Additionally preferred compounds of the invention include alicyclic or heteroalicyclic moiety, such as compounds of the following Formula VII:
Bxe2x80x94(CXY)m3xe2x80x94(Het)0 or 1xe2x80x94(CX1Y1)nxe2x80x94C(Z)pxe2x80x94(T)3xe2x88x92pxe2x80x83xe2x80x83VII
wherein B is an optionally substituted alicyclic or heteroalicyclic group preferably having about 5 to about 8 ring member, and may one or more endocyclic double bonds, provided the ring is not aromatic; each of T, X, Y, Xxe2x80x2, Yxe2x80x2, Z, n and p is defined as in Formula I above, m3 is an integer of from 0 (where the hetero atom is directly substituted with the cyclic hydrocarbon group) to 4, and preferably is 0, 1 or 2; and pharmaceutically acceptable salts thereof.
Additionally preferred compounds include those of the above Formula VII where the B group is preferably cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl, cyclohexadienyl, cyclopentynyl, or cyclohexynyl such as the compounds of the following Formula VIIa:
(R1)q2xe2x80x94Bxe2x80x94(CXY)m3xe2x80x94(Het)0 or 1xe2x80x94(CX1Y1)nxe2x80x94C(Z)pxe2x80x94(T)3xe2x88x92pxe2x80x83xe2x80x83VIIa
wherein R1 is the same as defined above in Formula II, each of X, Y, Xxe2x80x2, Yxe2x80x2, Z, g, n and p is defined as in Formula I above, m3 is the same as defined above in Formula VIII, and q2 is an integer from 0 (where the B group ring atoms are fully substituted with hydrogen) to 10, and preferably q2 is 0, 1, 2, or 3; and pharmaceutically acceptable salts thereof.
In a more preferred embodiment of the Formula VIIa shown above, R1 is hydroxyl; B is cyclohexyl or cyclopentyl; m3 and n are each 0; g is 1; Het is nitrogen; Z is hydrogen; q2 is 1; p is 2; and pharmaceutically acceptable salts thereof.
Additionally preferred compounds of the invention comprise an imide, such as a succinimide or phthalimide, in addition to a group T as defined above. For instance, preferred imide compounds of the invention include those of the following Formula VIII:
(Txe2x80x2)q3xe2x80x94Dxe2x80x94(Txe2x80x3)q4xe2x80x83xe2x80x83VIII
wherein Txe2x80x2 and Txe2x80x3 are each the same or different and are the same as defined for T in Formula I above;
D is an optionally substituted imide group such as a succinimide, phthalimide or naphthalic acid imide, optionally with a C1-6 alkylene linkage between D and either or both Txe2x80x2 or Txe2x80x3 groups; and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of Formula VIII above include those where Txe2x80x2 contains an oxygen that is directly linked to a nitrogen of the D group; Txe2x80x3 is carboxyl, sulfinyl or a sulfonic group; q3 and q4 are each 1; and pharmaceutically acceptable salts thereof.
Further preferred compounds of the invention are those of the following Formula IX:
(V)xe2x80x94(Cxe2x95x90O)xe2x80x94(Het)0 or 1xe2x80x94Arxe2x80x94(R1)q5xe2x80x83xe2x80x83IX
wherein V is a heteroalicyclic or heteroaromatic group having from 1 to 3 separate or fused rings, 5 to about 8 atoms in each ring, and 1-3 hetero (N, O or S) atoms in each ring; Ar, Het are each the same as defined above in Formula I; R1 is the same as defined above in Formula II; q5 is an integer from 0 (in which instance the Ar group is fully substituted with hydrogen) to 5, and preferably q5 is 0, 1, 2, or 3; and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of Formula IX include those where V is an optionally substituted furan, isoxazolyl, pyrole, imidazolyl, pyrazolyl, thienyl, isothiazolyl, furazanyl, or triazobenzene group; and/or Het is oxygen, if present.
Still further preferred compounds of the invention include those of the following Formula IXa, IXb, IXc, and IXd: 
wherein each of R3a, R3b, R3c and R3d is the same as the R1 group defined in Formula II above with the proviso that each of R3a, R3b, R3c and R3d can be the same or different; Het1 and Het2 are each independently N, O or S the same or different; each of Ar2a, Ar2b, Ar2c, and Ar2d is independently an optionally substituted carbocyclic aryl or optionally substituted heteroaryl group the same or different; V is the same as defined in Formula IX above; q6 is an integer from 0 (in which case the Ar2a group is hydrogen substituted) to 5, and preferably q6 is 0, 1, 2 or 3; q7 is the same as q6 with the proviso that q6+q7 is not greater than 5; q8 is an integer from 0 (in which case the Ar2b group is hydrogen substituted) to 5, and preferably q8 is 0, 1, 2 or 3; q9 is the same as q8 with the proviso that q7+q8 is not greater than 5; and pharmaceutically acceptable salts thereof. 
wherein R3e is the same as the R1 group defined in Formula II above, with the proviso that each of R3a, R3b, R3c, R3d and R3e is the same or different; q10 is an integer from 0 (in which case the Ar2a group is hydrogen substituted) to 5, and preferably q is 0, 1, 2 or 3; q11 and q12 are each independently the same as q10 defined above with the proviso that q10+q11+q12 is not be greater than 5; q13 is an integer from 0 (in which case the Ar2c group is hydrogen substituted) to 5, and preferably q13 is 0, 1, 2 or 3; q14 is the same as q13 defined above with the proviso that q13+q14 is not greater than 5; and pharmaceutically acceptable salts thereof. 
wherein R3f is the same as R1 as defined above in Formula II with the proviso that R3f can also be an optionally substituted cycloalkyl group having from about 5 to about 8 carbons, preferably about 5 to about 6 carbons, and R3f can be the same or different from each of R3a, R3b, and R3c as defined above; q7 is an integer from 0 (in which case the Ar2a group is hydrogen substituted) to 5, and preferably q7 is 0, 1, 2 or 3 with the proviso that q6+q7 in Formula IXc is not greater than 5; q15 is an integer from 0 (in which instance the carbon atom is bound to hydrogen) to 2; m4 is an integer from 0 (in which case the Ar2a group is substituted with Het1 or the (CXY) group is substituted with a carbon atom bound to the Ar2a, Het1, and R3f groups) to 4, and preferably 0, 1, or 2; and pharmaceutically acceptable salts thereof. 
wherein each of (V2a) and (V2b) is independently the same as V defined above in Formula IXd with the proviso that each of (V2a) and (V2b) can be the same or different and with the proviso that both V2a and V2b are not both 0; m6 is an integer from 0 (in which case the Ar2a group is directly bound to the xe2x80x94CHxe2x80x94 group) to 4, and preferably 0, 1, or 2; and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of Formula IXa above include those compounds in which V includes a pyridyl, pyrazinyl, pyrimidinyl, or triazine ring substituted with an optionally substituted carbocyclic aryl or optionally substituted heteroaryl, preferably a phenyl group.
Particularly preferred compounds of Formula IXb above include those where Ar2a, Ar2b and Ar2c are each substituted phenyl; V is an optionally substituted 4- or 5-pyrazolone group; each of q10, q11, q12 and q13 is 1; each of Het1 and Het2 is a nitrogen atom; R3a, R3b, and R3c are each halogen, preferably chlorine; and each R3d, R3e is an xe2x80x94NO2+ group; and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of Formula IXc above include those where Ar2a and Ar2b are each phenyl, R1f is an optionally substituted cyclopentyl or cyclohexyl group, each of q1, q2, q3, q4, q5, q6 is 1, each of Het1 and Het2 is a nitrogen atom, X and Y are both hydrogen; m, m1 and m2 are each 1, R1a, R1b, and R1e are each hydroxyl; and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of Formula IXd above include those where Ar3a is substituted phenyl; and R3a is halogen, preferably bromine; X and Y are both hydrogen; m6 is 1; each of V1a and V1b include at least one nitrogen atom, preferably an indolyl, isoindolyl, indazolyl, benzimdazole, or a triazobenzene group; and pharmaceutically acceptable salts thereof.
Still additional preferred TF antagonist compounds of the invention include both aromatic and alicyclic groups, such as compounds of the following Formula X:
Ar3xe2x80x94(CXY)m7xe2x80x94(Het)0 or 1xe2x80x94(V)xe2x80x83xe2x80x83X
wherein Ar3 is an optionally substituted carbocyclic aryl or heteroaryl group, preferably an optionally substituted quinoline group; each of X, Y, and Het is the same as defined above in Formula I with the proviso that X and Y can also join together to form a carbonyl group; m7 is an integer from 0 (in which case Ar3 is directly bound to Het) to 4, and preferably is 0, 1, or 2; V is the same as defined above in Formula IXa; and pharmaceutically acceptable salts thereof.
The invention also includes phosphonate compounds that do not include aromatic substitution. Such phosphonate compounds also have been disclosed in U.S. application Ser. No. 09/406,269, filed Sep. 24, 1999, as discussed above. Preferred non-aromatic phosphonate compounds will have one, two or three phosphonate groups (i.e. PO3), and 3, 4, 5 or 6 to about 25 carbon atoms, as non-cyclic and/or alicyclic moieties with one or more non-aromatic double or triple carbon-carbon double or triple bonds, typically zero, one two or three carbon-carbon double or triple bonds. The compounds also may contain one or more hetero atoms (N, O or S), typically, zero, one, two or three such hetero atoms. For example, as disclosed in said U.S. application Ser. No. 09/406269, alendronic acid (Fosamax) is an effective TF antagonist compound.
Preferred compounds of the invention also include nitrogen ring compounds, particularly nitrogen ring compounds that contain at least one additional hetero atom (N, O or S), typically one such additional hetero atom and the other ring members being carbon. Typically, the ring compound will be non-aromatic, although it may include one or more additional separate or fused rings that may be aromatic or non-aromatic. Typically, the nitrogen-containing ring will have 5 to about 10 ring atoms, more typically 5, 6, 7, or 8 ring atoms, even more typically 5 or 6 ring atoms. Such nitrogen ring compounds include those of the following Formula XI: 
wherein R1, R2, R3, X and Y each may be independently the same as defined for R1 of Formula II above; or R1 and R2 of this Formula XI may be taken together to form a fused carbocyclic aryl (e.g. phenyl or naphthyl), alicyclic (e.g. cyclohexyl), heteroalicyclic or heteroaromatic group having 1-3 fused or separate rings. The heteroalicyclic and heteroaromatic groups will have suitable heteroaromatic or heteroaryl groups will have 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to about 3 hetero atoms (N, O or S), and include e.g. courmarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimdinyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, and benzothiazol;
Het is oxygen, optionally substituted N, S, S(O) or S(O)2, and preferably is oxygen;
X is 1 (5-membered ring), 2 (6-membered ring), 3 (7-membered ring), or 4 1 (8-membered ring); and pharmaceutically acceptable salts thereof.
Preferred compounds of the invention also include substituted piperazine compounds, such as compounds of the following Formula XII: 
wherein each R1 is independently the same as defined for R1 of Formula II above;
x is an integer of from 1 to 10; and pharmaceutically acceptable salts thereof
Additional compounds of the invention bind tissue factor (TF) so that FX does not effectively bind to the TF/factor VIIa complex whereby FX is not effectively converted to its activated form (FXa). Preferred compounds of the invention can inhibit TF function by effectively blocking FX binding access to TF molecules. References herein to xe2x80x9ccompounds of the inventionxe2x80x9d are inclusive of compounds of Formulae I through XII.
In preferred aspects, the invention provides methods for inhibiting blood coagulation and blood clot formation in a mammal, methods for inhibiting thrombin generation in a mammal, and methods for treating or preventing thromboembolic disorders in a mammal. The methods of the invention in general comprise administering to a mammal, such as a primate particularly a human, a therapeutically effective amount of a compound of the invention.
Compounds of the invention are particularly useful to alleviate various diseases impacted by tissue factor (TF). By the term xe2x80x9cimpactedxe2x80x9d is meant that the severity or duration of the disease is increased by presence of the TF according to the recognized assays or tests. Particular diseases include thromboses, especially to prevent or inhibit restenosis, or other thromboses following an invasive medical procedure such as arterial or cardiac surgery (e.g., angioplasty), including for prophylaxis of deep vein thrombosis associated with orthopedic or other surgery. Compounds of the invention also can be employed to reduce or even effectively eliminate blood coagulation arising from use of medical implementation (e.g., a catheter, stent or other medical device). Compounds of the invention also will be useful for prophylaxis for long term risk for myocardial infarction. Compounds of the invention also will be useful for treatment of thrombotic conditions that may be associated with acute promyelocytic leukemia, diabetes, multiple myelomas, disseminated intravascular coagulation associated with septic shock, purpura fulminanas associated infection, adult respiratory distress syndrome, unstable angina, and thrombotic complications associated with aortic valve or vascular prosthesis.
Additional uses for the present compounds include use in the prevention and treatment of atherosclerosis, inflammation, and as an anti-angiogenic agent, especially to treat cancers, particularly solid cancers such as cancers residing in the lung, breast, liver, brain or other tissue.
Compounds of the invention also can be employed as an anti-coagulant in extracorporeal circulation of a mammal, particularly a human subject. In such methods, one or more compounds of the invention is administered to the mammal in an amount sufficient to inhibit blood coagulation prior to or during extracorporeal circulation such as may be occur with cardiopulmonary bypass surgery, organ transplant surgery or other prolonged surgeries.
Compounds of the invention also can be employed in in vivo diagnostic methods including in vivo diagnostic imaging of a patient.
Compounds of the invention also can be used in in vitro assays, e.g. to selectively inhibit Factor X activation. Such assays of the invention will be useful to determine the presence or likelihood of a patient having blood coagulation or a blood clot.
Pharmaceutical compositions also are provided comprising an effective amount of one or more compounds of the invention and a pharmaceutically acceptable carrier.
Other aspects of the invention are discussed infra.